1. Field of the Invention
This invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease.
References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., Biochem. Biophys. Res. Commun. (1984) 120:885-890. 
2 U.S. Pat. No. 4,666,829, issued May 19, 1987, to G. G. Glenner et al., entitled xe2x80x9cPolypeptide Marker for Alzheimer""s Disease and Its Use for Diagnosis.xe2x80x9d
3 Selkoe, Neuron. (1991) 6:487-498.
4 Goate, et al., Nature (1990) 349:704-706.
5 Chartier Harlan, et al., Nature (1989) 353:844-846.
6 Murrell, et al., Science (1991) 254:97-99.
7 Mullan, et al., Nature Genet. (1992) 1:345-347.
8 Schenk, et al., International Patent Application Publication No. WO 94/10569, xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, published 11 May 1994.
9 Selkoe, Scientific American, xe2x80x9cAmyoid Protein and Alzheimer""s Diseasexe2x80x9d, pp. 2-8, November, 1991.
10 Yates et al., U.S. Pat. No. 3,598,859.
11 Tetrahedron Letters 1993, 34(48), 7685.
12 R. F. C. Brown et al., Tetrahedron Letters 1971, 8, 667-670.
13 A. O. King et al., J. Org. Chem. 1993, 58, 3384-3386.
14 U.S. Provisional Application Serial No. 60/019,790, filed Jun. 14, 1996.
15 R. D. Clark et al., Tetrahedron 1993, 49(7), 1351-1356.
16 Citron, et al., Nature (1992) 360:672-674.
17 P. Seubert, Nature (1992) 359:325-327.
18 Hansen, et al., J. Immun. Meth. (1989) 119:203-210.
19 Games et al., Nature (1995) 373:523-527.
20 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555.
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
2. State of the Art
Alzheimer""s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHW A-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (xcex2AP) or sometimes Axcex2, Axcex2P or xcex2/A4. xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,8292.
Molecular biological and protein chemical analyzes have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis in vivo.
Compounds which inhibit xcex2-amyloid peptide release and/or its synthesis in vivo are disclosed in U.S. patent application Ser. No. 08/996,422, filed Dec. 22, 1997, now U.S. Pat. No. 6,635,632 entitled xe2x80x9cCycloalkyl, Lactam, Lactone and Related Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting xcex2-Amyloid Peptide Release, and/or its Synthesis by Use of Such Compounds,xe2x80x9d the disclosure of which is incorporated herein by reference in its entirety. The present invention is directed to deoxy derivatives of such compounds.
This invention is directed to the discovery of a class of compounds which inhibit xcex2-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition.
Accordingly, in one of its composition aspects, the present invention provides compounds of formula I: 
wherein
W is a cyclic group selected from the group consisting of: 
wherein
ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
ring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
Y is represented by the formula: 
provided that at least one Y is xe2x80x94(CHR2xe2x80x2)axe2x80x94NHxe2x80x94;
R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
each R2xe2x80x2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;
Q is oxygen, sulfur, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
Z is represented by the formula xe2x80x94Txe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94, wherein T is selected from the group consisting of a bond covalently linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, oxygen, sulfur and xe2x80x94NR6, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl group;
Xxe2x80x2 is hydrogen, hydroxy or fluoro,
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;
a is an integer from 2 to about 6;
f is an integer from 0 to 2;
m is an integer equal to 0 or 1;
n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof.
A subgenus of compounds within formula I, wherein m=1 and n=1 can be represented by formula IA: 
wherein Zxe2x80x2 is xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, xe2x80x94Txe2x80x94CH2xe2x80x94, or xe2x80x94Txe2x80x94C(O)xe2x80x94, wherein T is selected from the group consisting of oxygen, sulfur, and xe2x80x94NR6, wherein R6 is hydrogen, acyl, alkyl, aryl, or heteroaryl; Xxe2x80x2 is hydrogen, hydroxy, or fluoro, and Xxe2x80x3 is hydrogen, hydroxy, or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group; and
R1, R2, W, and a are as defined hereinabove with respect to formula I; and pharmaceutically acceptable salts thereof.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the formula I above.
Additionally, in one of its method aspects, this invention is directed to a method for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of xcex2-amyloid peptide.
Because the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8,9, the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In formula I above, rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. Still more preferably, rings A and B are independently aryl.
Particularly preferred A and B rings include, by way of example, phenyl, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like.
Preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, morpholino and the like.
When m is zero (i.e., there is a covalent bond from R1 to NH), R1 is preferably aryl (including substituted aryl) or heteroaryl (including substituted heteroaryl). In this embodiment, further preferred R1 groups include
(a) phenyl,
(b) a substituted phenyl group of the formula: 
wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
Rb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rbxe2x80x2 are either both hydrogen or both substituents other than hydrogen,
(c) 2-naphthyl,
(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,
(e) heteroaryl,
(f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the xe2x80x94NH group, and
(g) alkyl.
When m is zero, particularly preferred substituted phenyl R1 groups include mono-, di- and tri-substituted phenyl groups including 3,5-disubstituted phenyls such as 3,5-dichlorophenyl, 3,5-difluorophenyt, 3,5-di(trifluoromethyl)-phenyl, etc.; 3,4-disubstituted phenyls such as 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro4-iodophenyl, 3,4-methylenedioxyphenyl, etc.; 4-substituted phenyls such as 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-ethoxy)ethylphenyl, etc., 3,4,5-trisubsituted phenyls such as 3,4,5-trifluorophenyl, 3,4,5-trichlorophenyl, etc.
Specific R1 groups for when m is zero include 3,4-dichlorophenyl, 4-phenylfurazan-3-yl, and the like.
When m is zero, other preferred R1 substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, phenyl, and the like.
When m is one, preferred R1 groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.; substituted aryl groups such as monosubstituted phenyls (preferably substituents at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and trisubstituted phenyls (preferably substituents at the 3,4,5 positions). Preferably, the substituted phenyl groups do not include more than 3 substituents. Examples of substituted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
When m is one, other preferred R1 groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CHxe2x95x90CHCH2CH2CH(CH3)xe2x80x94, xcfx86C(O)CH2xe2x80x94, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2xe2x80x94, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CHxe2x95x90CHxe2x80x94, CH3CH2CHxe2x95x90CHxe2x80x94, (4-chlorophenyl)C(O)CH2xe2x80x94, (4-fluorophenyl)C(O)CH2xe2x80x94, (4-methoxyphenyl)C(O)CH2xe2x80x94, 4-(fluorophenyl)-NHC(O)CH2xe2x80x94, 1-phenyl-n-butyl, (xcfx86)2CHNHC(O)CH2CH2xe2x80x94, (CH3)2NC(O)CH2xe2x80x94, (xcfx86)2CHNHC(O)CH2CH2xe2x80x94, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2xe2x80x94, 4-methoxyphenyl-C(O)CH2xe2x80x94, phenyl-C(O)CH2xe2x80x94, CH3C(O)N(xcfx86)-, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2xe2x80x94, 4-fluorophenyl-C(O)CH2xe2x80x94, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2xe2x80x94, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2xe2x80x94, trans-styryl, H2NC(O)CH2CH2xe2x80x94, 2-trifluoromethylphenyl-C(O)CH2, xcfx86C(O)NHCH(xcfx86)CH2xe2x80x94, mesityl, CH3CH(xe2x95x90NHOH)CH2xe2x80x94, 4-CH3-xcfx86-NHC(O)CH2CH2xe2x80x94, xcfx86C(O)CH(xcfx86)CH2xe2x80x94, (CH3)2CHC(O)NHCH(xcfx86)xe2x80x94, CH3CH2OCH2xe2x80x94, CH3OC(O)CH(CH3)(CH2)3xe2x80x94, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, xcfx86SO2CH2xe2x80x94, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2xe2x80x94 and N-pyrrolidinyl.
When present, R2 is preferably selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
Each R2xe2x80x2 is preferably (and independently) selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
Particularly preferred R2 and R2xe2x80x2 substituents (when R2xe2x80x2 is other than hydrogen) include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol-4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2-(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like. Preferably, R2xe2x80x2 is methyl.
Preferably, R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. In another preferred embodiment, R3 is alkyl, substituted alkyl or aryl. More preferably, R3 is alkyl.
Particularly preferred R3 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
When present, R4 is preferably alkyl or substituted alkyl.
R5 is preferably alkyl; substituted alkyl; phenyl; substituted phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl and the like; cycloalkyl, such as cyclohexyl and the like; or heteroaryl or heterocyclic, such as 1-piperdinyl, 2-pyridyl, 2-thiazyl, 2-thienyl and the like.
Preferably, f is 0 or 1. More preferably, f is 0.
When Y is the group xe2x80x94(CHR2xe2x80x2)axe2x80x94NHxe2x80x94, the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and still more preferably a is equal to 2. In a preferred embodiment, Y has the formula xe2x80x94CHR2xe2x80x2xe2x80x94CH2xe2x80x94NHxe2x80x94, where R2xe2x80x2 is as defined herein, including the described preferred embodiments.
In one preferred embodiment of this invention, W is a cyclic group of the formula: 
wherein
each R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl,
xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl;
each R7 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl,
xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
p is an integer from 0 to 4; q is an integer from 0 to 4.
Preferably, R6 and R7 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy. More preferably, when present, R6 and R7 are fluoro.
R8 is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More preferably, R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
Particularly preferred R8 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
In another preferred embodiment of this invention, W is a cyclic group of the formula: 
wherein R6, R7, and p are as defined herein and r is an integer from 0 to 3.
In still another preferred embodiment of this invention, W is a cyclic group of the formula: 
wherein R6 and p are as defined herein.
In yet another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6 and p are as defined herein.
In still another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8 and p are as defined herein; and
each R9 is independently selected from the group consisting of alkyl, substituted alky, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; and g is an integer from 0 to 2.
When present, R9 is preferably alkyl or substituted alkyl.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8, R9, g and p are as defined herein.
In yet another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8, R9, g and p are as defined herein.
In still another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, each R8 and p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, each R8, R9, g and p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8 and p are as defined herein; and
R10 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R10 and p are as defined herein; and
D-E is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and xe2x80x94Nxe2x95x90CHxe2x80x94.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8, R9, g and p are as defined herein; and
Q is oxygen, sulfur, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R6, R8 and p are as defined herein.
In another preferred embodiment of this invention, W is a cyclic ring of the formula: 
wherein R8 is as defined herein.
In the above formulae, preferably each R6 is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R7 is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R8 is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; each R9 is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q and r are 0 or 1. More preferably, g, p, q and r are 0.
Compounds of this invention include, by way of example, the following: 
i.e., 5S-[Nxe2x80x2-(2S-hydroxy-3-methylbutyryl)-2S-aminoprop-1-yl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
The products of this invention include mixtures of R,S enantiomers at any stereochemical center. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. In the formulas set forth herein, a mixture of R,S enantiomers at the stereochemical center is sometimes indicated by a squiggly line as per convention. Othertimes, no stereochemical designation is made at the stereochemical center and this also infers that a mixture of enantiomers is present.
Also included within the scope of this invention are prodrugs of the compounds of formula I above including acylated forms of alcohols and thiols, aminals of one or more amines, and the like.